Cytokines Before Targeted Drugs in Metastatic RCC?

Janis C. Kelly

February 18, 2010

February 18, 2010 — As experts continue to work on ways to make the best use of targeted therapies in metastatic renal cell carcinoma (RCC), new data on older drugs confirm that adding interleukin (IL)-2 and fluorouracil to interferon alfa-2a provides no survival advantage over treatment with interferon alone.

In their paper published online February 11 in The Lancet, Marten E. Gore, MD, and colleagues report the results of an open-label randomized multicenter trial, which found that neither overall survival nor progression-free survival improved with the 3-drug regimen. Dr. Gore is from the Department of Medicine, Royal Marsden Hospital NHS Trust in London, United Kingdom. The trial was conducted at 50 centers in the United Kingdom, Belgium, Denmark, Germany, Holland, and Slovakia.

However, the researchers did find complete responses in 2% of patients in both treatment group.

There may be a group — probably small — that should receive cytokines first rather than targeted agents"

"Targeted agents are the standard of care for the general metastatic renal cell cancer population. However, there may be a group — probably small — that should receive cytokines first rather than targeted agents. We now need to find them," Dr. Gore told Medscape Oncology.

A total of 502 treatment-naive patients diagnosed with advanced metastatic RCC were randomized to receive interferon alfa-2a alone 3 times per week until progression or unacceptable toxic effects; and 504 patients were randomized to receive combination therapy (no more than 2 cycles) with interferon alfa-2a, IL-2, and fluorouracil.

The primary end point was overall survival. Secondary outcomes were progression-free survival, toxicity, quality of life, and response to treatment.

Median follow-up was just over 3 years. Median overall survival was 18.8 months for patients receiving interferon alfa-2a and 18.6 months for those receiving combination therapy. Serious adverse events were reported in 113 (23%) patients receiving interferon alfa-2a and in 131 (26%) receiving combined treatment.

As noted, there were complete responses in 2% of patients in each group. In addition, there were partial responses in 12% of those in the interferon alfa-2a group and in 19% of those in the combination group.

The authors note that their response rate for combination treatment (23%) was lower than that reported earlier (Br J Cancer 2001;85:1130-1136), but that many of those patients received 3 cycles of combination treatment. Some clinicians might feel that the current study's 2-cycle protocol represents undertreatment, suggested Dr. Gore and his coauthors.

"Most investigators feel that 3 cycles of triple therapy is too much for most patients and is therefore undoable; it is one of those criticisms that is not unreasonable. It's a matter of opinion whether we were being too cautious. During the design phase, we did consult very widely, and the vast majority of colleagues were happy to stick at 2 cycles," Dr. Gore said.

Ongoing Need to Match Patients and Therapies

Patient selection remains to be addressed with the use of cytokines, suggested Dr. Gore.

"Triple regimens were slightly better handled and tolerated than expected, and the study confirmed that durable complete remissions are possible with cytokines at normal doses, not just with high doses of [intravenous] IL-2, although possibly at a lower rate. In addition, the study confirmed the need to have patient selection to identify those who might gain this benefit," he said.

Kim Margolin, MD, from the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle, was asked by Medscape Oncology to comment on this study. Dr. Margolin also served on the National Comprehensive Cancer Network panel that developed the current guidelines for treating RCC.

According to Dr. Margolin, "this is a very large and definitive study that, not surprisingly, demonstrates that combination therapy, as pioneered many years ago by [Jens Atzpodien, MD], does not enhance survival overall, despite what appears to be a small advantage in response rate and durable responses — the latter occurring so rarely in both groups that the statistical significance was not even noted.

"The data from this study fully support those of others and the general stance of the renal cancer community that combination therapy of this type should not be used, nor should single-agent [interferon alfa] be used routinely for metastatic RCC. Of course, the study could also be faulted for its lack of attention to details that have since assumed importance, such as nephrectomy status and histology, although the former was a stratification factor in randomization," Dr. Margolin added.

Dr. Margolin also point out that the study should be interpreted in context: it was done during a period in which today's targeted agents were not commercially available in many places.

"I would continue to support the recommendation that the best treatment for metastatic RCC is participation in a clinical trial. Currently, the trials are generally focused on looking for differences between available single agents or exploring the potential superiority (and tolerance) of thoughtfully designed combination regimens, and learning which molecularly and immunologically defined groups are more likely to benefit from which types of therapy. "One size" does not "fit all," Dr. Margolin said.

Dr. Gore and Dr. Margolin have disclosed no relevant financial relationships.

Lancet. 2010. Published online February 11, 2010. Abstract

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